Phase 2 study of ASTX727 (cedazuridine/decitabine) plus venetoclax (ven) in patients with relapsed/refractory acute myeloid leukemia (AML) or previously untreated, elderly patients (pts) unfit for chemotherapy.
Authors: Farhad Ravandi, Tareq Abuasab, Yesid Alvarado Valero, Ghayas C. Issa, Rabiul Islam, Nicholas James Short, Musa Yilmaz, Nitin Jain, Lucia Masarova, Steven Mitchell Kornblau, Elias Jabbour, Naveen Pemmaraju, Guillermo Montalban Bravo, Sherry Pierce, Courtney Denton Dinardo, Tapan M. Kadia, Naval Guastad Daver, Marina Konopleva, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2022)

7037 Background: ASTX727, is an oral formulation of the fixed dose combination of decitabine and cytidine deaminase inhibitor cedazuridine (100 mg/35 mg). We investigated whether a total oral therapy regimen of ASTX727+ven is feasible and safe. Methods: Pts aged ≥18 years (yrs) with relapsed/refractory AML (R/R) or pts with AML aged ≥ 75 or 18 -74 with comorbid conditions prohibiting intensive chemotherapy were eligible to participate (frontline-FL). Other eligibility criteria included adequate renal and hepatic function, and an ECOG performance status (PS) of≤2. ASTX727 is administered daily on days 1‐5 of each cycle and ven on days 1‐28 of the first cycle after a dose ramp up of 100-200-400 mg over 3 days (with tumor lysis prophylaxis precautions and with ven dose adjustments as needed). A bone marrow exam is performed on day 21±3 days and ven is held if blasts &lt; 5% to allow count recovery. Cycles are repeated every 4-8 weeks and ven is administered for 21 days in subsequent cycles. Results: Between March 2021 and January 2022, 28 pts (15 FL and 13 R/R) have been treated on the study. The median age is 75 yrs (range, 47-90) with FL cohort 81 and R/R cohort 72. 9 FL pts (60%) were ≥80 and 5 (30%) 70-80 yrs. In R/R cohort 9 pts (69%) were 70-80 yrs. The median PS is 2 (range 0-3) and in the R/R cohort, the median number of prior treatments is 2 (range, 1-4). In the FL cohort 5 (33%) had normal and 6 (40%) a complex karyotype; 3 had other. In the R/R cohort, 15% had normal karyotype, 46% complex and 31% others. Mutations of note in the frontline cohort were RUNX1 (33%), ASXL1 (33%), DNMT3A (7%), TET2 (40%) and TP53 (20%). The overall response rate (ORR) including complete response (CR), CR with incomplete count recovery (CRi) and morphological leukemia free state (MLFS) in the FL cohort is 61% (4 CR, 4 CRi, 1 MLFS and 3 non-responders). 3 pts received only one day of therapy for severe adverse events unrelated to therapy (1 due to ischemic stroke, 1 septic shock and 1 debilitation) and were not evaluable for response. In the R/R cohort, the ORR was 45% (2 CR, 2 CRi, 2 MLFS with 5 non-responders and 2 not evaluable). The median number of cycles received is 2 (range, 1-5) for both cohorts. With a median follow-up of 5 months, the median survival for the FL cohort has not been reached (range, 0.6 – 7.3) and is 7.2 (range, 0.8-7.3) months for the R/R cohort. Grade 3 or higher adverse events directly attributable to therapy were mainly myelosuppression-related and included neutropenic infections in 3 (11%) and elevation of liver enzymes in 1 (4%) pt. Conclusions: Total oral therapy of ASTX727+ven is safe and feasible, particularly in the advanced elderly population, and demonstrates significant efficacy in pts unfit for chemotherapy both in the FL and R/R settings. Clinical trial information: NCT04746235.